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Home , Renal physiology

Update in Anaesthesia

Renal Physiology

Katie Wallace Correspondence Email: [email protected]

Introduction like extension of the tubule called the Bowman’s Summary The is a complex organ with several different capsule The major functions of the functions. One way to remember these functions is to • The proximal convoluted tubule (PCT) kidneys can be identified think about a patient who has chronic renal failure. by knowledge of the The main features are: • The descending thin limb of the pathological changes seen in renal failure. The 1. Salt and retention with oedema and • The ascending thin and thick limb of the loops of Henle kidney has important hypertension roles in salt and water, 2. Uraemia • The vasa recta, which is a series of specialised acid-base, and . These 3. Hypercalcaemia and hyperphosphataemia which wrap around the loop of Henle functions are described, 4. Acidosis and hyperkalaemia • The distal convoluted tubule (DCT) including the role of the 5. Anaemia. countercurrent multiplier • The collecting duct. and exchange systems of The main functions of the kidney are therefore: The glomeruli sit within the and drain the loop of Henle. Where into the PCT. This then drains into the descending relevant, clinical examples 1. Salt and water balance or homeostasis are used to demonstrate limb of the loop of Henle, which descends down 2. Toxin removal the multiple roles of the through the medulla. It then turns back on itself, kidney. 3. Calcium and homeostasis becoming the ascending limb, and returns to the 4. Acid–base homeostasis cortex before becoming the DCT. The DCT drains 5. Stimulation of erythropoesis Homeostasis means ‘maintenance of the internal environment’ of the body within closely regulated limits. The functions of the kidneys are necessary to maintain this constant environment despite great variation in oral intake and the external environment.

BASIC STRUCTURE OF THE KIDNEYS The kidney has several layers starting from the outer renal cortex moving deeper to the outer medulla and then to the inner medulla. The specialised structure within the kidney is the . Each kidney contains Katie Wallace approximately one million Specialist Trainee . Each nephron consists Department of Anaesthesia of: Royal Devon and Exeter • A , which in turn NHS Foundation Trust consists of a tuft and Devon EX5 5DW a specialised enclosed pouch Figure 1. Detailed anatomy of the kidney and nephron UK

Update in Anaesthesia | www.worldanaesthesia.org page 60 into a collecting duct which descends back down through the medulla ) this is one of the renal mechanisms for eliminating drugs so that can drain into the renal pelvis and ureter. Humans have from the body. The majority of renal elimination of drugs from the a mixture of short (cortical nephrons) and long (juxta-medullary) body however is by . nephrons - eighty-five per cent are short in humans. In general the greater the proportion of long loops or length of loop the greater the Loop of Henle concentrating ability (for example dogs are able to concentrate urine The human body has no active pump for water, which can only move to greater than 3000mmosm.l-1, and some desert animals to greater across a membrane by osmosis. The role of the Loop of Henle is to than 5000 mmosm.l-1) create an increasing concentration gradient in the interstitial tissues as the loop passes deeper into the medulla. A gradient from about FUNCTIONS OF THE KIDNEY 285mosm.l-1 in at the beginning of the loop to 1200mosm.l-1 at the apex of the loop is achieved. The collecting ducts pass through this Glomeruli osmotic gradient and so, under the influence of antidiuretic The glomerulus is the filter unit of the nephron. It passively lets (ADH), water can be retained. The loops of Henle constitute a water, amino acids, and other free pass through its countercurrent system - the ascending and descending limbs of membranes and into the tubule system, but not charged proteins, each loop are parallel, counter to (i.e. opposite in flow) and in close large proteins or cells. The unique basement membrane, which is proximity to each other. at the interface of the capillaries and Bowman’s capsule, allows this to happen. Glomerular filtration produces up to 125ml filtrate per There are 3 sections to the loop of Henle: minute, most of which needs to be quickly reabsorbed. 1. Thin descending limb Proximal convoluted tubule (PCT) 2. Thin ascending limb The PCT is responsible for the majority of the . There are four different mechanisms by which solute transport occurs: 3. Thick ascending limb

1. Passive which occurs across a membrane down an The countercurrent system consists of: electrochemical gradient, e.g. sodium and ions. • A countercurrent multiplier (the loop of Henle) which sets up 2. which is also passive but is more selective as an increasing gradient of osmolality as you go to the bottom of it requires the interaction between an and a membrane-bound the loop. specific carrier protein, e.g. sodium/ cotransporter. • A (the vasa recta) which maintains this gradient. ADH acts to allow uptake of water from the collecting 3. Passive diffusion through a membrane channel or pore, e.g. ducts. The osmotic gradient would otherwise gradually diminish in the collecting duct. as water is reabsorbed by osmosis. 4. against an electrochemical gradient by an energy requiring pump, e.g. the potassium- ion antiporter in Countercurrent multiplier the collecting duct. Essentially, sodium and chloride (Na+ and Cl-) leave the ascending limb, which is impermeable to water which therefore cannot follow. Some transporters within the PCT are responsible for secretion Deep in the medulla, Na+ and Cl- leave by passive diffusion, however of weak acids and bases. As drugs can be weak acids or bases (e.g. this passive diffusion is not sufficient to maintain such asteep gradient, so in the thick ascending limb sodium is actively pumped Table 1. Substances reabsorbed in the PCT out into the interstitium. Water does move out of the descending limb into the interstitium by osmosis and this leaves the fluid within Substance Approximate % reabsorbed in PCT the descending limb gradually increasing in osmolality as it moves deeper into the medulla towards the apex of the loop. Water 65

Sodium 60 It is only as enters the ascending loop that it starts to become less concentrated as Na+ and Cl- are actively pumped out Potassium/Chloride/ 80 (which is where we started). In effect, Na+ and Cl- are circulating around the bottom part of the loop which generates the high 100 osmolality in the interstitium. Amino acids 100 Countercurrent exchange Calcium 60 The multiplier is self-perpetuating until ADH allows water tobe reabsorbed, thereby lowering the osmolality in the interstitium. The Phosphate 80 vasa recta are also countercurrent in their lay-out and they act in a Urea 50 very similar way to maintain the hypertonicity of the interstitium at the bottom of the loop.

page 61 Update in Anaesthesia | www.anaesthesiologists.org Figure 2. The function of the loop of Henle in concentration of urine

Na+ and Cl- diffuse from the ascending vasa into the descending vasa 2. Different segments of the loop have different permeabilities to and recirculate around the lowest parts of the loops. At the same water and sodium. time water diffuses from the descending vasa across to the ascending 3. Reabsorbed water is rapidly removed from the interstitium into vasa. the systemic circulation via the vasa recta.

The role of urea 4. Sodium which is reabsorbed is effectively ‘trapped’ in the The other major factor in generation of the hypertonic medulla interstitium. is the fact that the collecting ducts are impermeable to urea until 5. The ascending and descending limbs of the same nephron the portions deep within the medulla, by which time (after water run parallel to each other with the filtrate running in opposite reabsorption) the urea concentration is very high. When urea reaches directions. this part of the collecting duct, ADH sensitive urea channels allow it to move into the interstitum down a concentration gradient and this 6. The unique arrangement of the supply (the vasa recta) is an further increases the osmolality of the interstitium. Some of the urea essential component in this system. diffuses back into the filtrate in the thin limbs of the loop of Henle Distal convoluted tubule (DCT) and some stays within the interstitium. The DCT is where the final fine tuning of the reabsorption of many In summary the important points about the counter current ions such as sodium, calcium, phosphate, potassium, and acid base multiplier system are: balance is achieved.

1. It is driven by the active reabsorption of the sodium in the thick Collecting duct ascending limb. The collecting duct passes down through the concentration gradient

Update in Anaesthesia | www.worldanaesthesia.org page 62 generated by the countercurrent system. It has varying permeability Altering the radius of either or both of these vessels will alter the to water depending on the amount of antidiuretic hormone present pressure within glomerulus. This is called autoregulation, and is and therefore is responsible for concentrating urine. It is also involved achieved with the help of the macula densa, a group of specialised with acid secretion (see below) cells which sit with in the distal part of the ascending limb of the loop of Henle. They are also in close proximity to the afferent and RENAL BLOOD FLOW efferent arterioles. The capillaries and the macula densa together Twenty per cent of the cardiac output (about 1200ml.min-1) goes make up the juxtaglomerular complex. If the falls to the kidney. The amount of blood flow directly affects the rate at there is a decrease in the renal blood flow, and a decreased volume which the glomerulus can filter (the glomerular filtration rate - GFR) of filtrate. This causes a decreased delivery of sodium and chloride and subsequently the amount of filtrate produced. to the macula densa. The macula densa senses this and stimulates the local release of a hormone, . Renin converts circulating Rate of removal = blood flow to organ x arteriovenous difference (a-v) angiotensinogen to I. Angiotensin I is carried to the lungs of substance in concentration of substance where it is converted to angiotensin II by angiotensin converting (ACE). Angiotensin II is then taken back into the systemic So to measure renal plasma flow a substance with high extraction circulation and has its effects as outlined in Figure 4. is used, for example para-amino hippuric acid (PAH):

Rate of removal in urine (u) = urine concentration x urine volume

Venous concentration is close to zero, so a-v = a

So renal plasma flow (RPF) = u x v x 1 a 0.9

(PAH has an of 90%)

For renal blood flow, multiply by 1 1 – haematocrit

Similarly for glomerular filtration rate (GFR), choose a substance which is freely filtered at the glomerulus and neither secreted or re-absorbed, e.g. or . Figure 4. The renin-angiotensin system GFR = of inulin = u x v where p = plasma concentration p Clinical points Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit The = GFR = 0.16-0.2 production and so can impair afferent arteriolar dilatation, reducing RPF GFR. It is for this reason that NSAIDs should be avoided in patients with renal impairment and those who are hypovolaemic and reliant on afferent vasodilatation to maintain GFR.

Patients with renal artery stenosis rely on high efferent arteriolar ORGAN tone to maintain a high filtration pressure across the glomerulus. ACE inhibitor drugs are contraindicated in these patients since they Venous Arterial inhibit efferent arteriolar constriction (by inhibiting angiotensin II concentration concentration production) and so GFR is dramatically reduced, with consequent (v) (a) deterioration in renal function.

Amount The angiotensin II has four effects: excreted, 1. Generalised vasoconstriction causing increased systemic vascular extracted or resistance and increasing the blood pressure. metabolised. 2. Constriction of both the afferent and efferent arteriole but constricting the efferent more. This then increases the differential Figure 3. The Fick principle can be used to calculate blood flow for any pressure across the glomerular capillary tuft and increases the organ system using a substance that is removed (excreted, extracted or GFR. metabolised) by the organ 3. Stimulation of the release of from the adrenal gland, The blood flow into the glomerulus is via the afferent arteriole and which stimulates the reabsorption of sodium from the DCT and the blood flow out of the glomerulus is by the efferent arteriole. collecting duct.

page 63 Update in Anaesthesia | www.anaesthesiologists.org 4. Stimulates via an action on the . Box 1. ADH and the renin-angiotensin systems are demonstrated by the body’s response to different haemodynamic challenges: Other substances such as nitric oxide and which vasodilate are also released locally in response to altered pressure 1000ml 0.9% saline intravenously - a response to a small within the capillary tuft, but the exact mechanisms are poorly increase in volume understood. This is a volume load but it is isotonic. The volume expansion is initially 1000ml which distributes quickly into the WATER HOMEOSTASIS - about 250ml stays in the intravascular volume, the remainder fills the interstitial space: Water balance is controlled by antidiuretic hormone (ADH). ADH is released from the posterior pituitary in response to three stimuli: → ↑ blood volume stimulates cardiopulmonary stretch receptors (right atrium) 1. Increased osmolality in the hypothalamus, → posterior pituitary → ↓ADH secretion → ↓ thirst and 2. Decreased plasma volume (cardiopulmonary receptors in the 1000ml blood intravenously - a response to a large increase in right atrium and pulmonary vessels), volume This volume stays in the intravascular compartment. 3. Angiotensin II. Acute response Osmoreceptors located in the hypothalamus sense an increase → stimulates the baroreceptors of the arterial system (carotid & aortic in and stimulate the release of ADH. Reduced sinuses) blood pressure is sensed by the atrial stretch receptors and arterial → via the glossopharyngeal and vagus nerves baroreceptors, which also stimulate the release of ADH. ADH release → reflex↓ cardiac output and ↓ vascular tone causes an increase in the number of water channels called , Slower response with in the collecting duct. This facilitates greater water reabsorption → ↓ activation of renin-angiotensin system by osmosis, as the collecting ducts pass through the concentration → ↓ aldosterone secretion gradient generated by the loop of Henle. 1000ml 5% glucose intravenously or water orally - a response to a decrease in osmolality SODIUM BALANCE This constitutes less of a volume load since it is distributed into the Approximately 60% of sodium is reabsorbed in the PCT, 20% in the entire . One twelfth stays in the intravascular space (83ml). loop of Henle and 5% in the DCT and collecting duct. Oral water is similar since it is rapidly absorbed form the stomach However it does cause plasma dilution and ↓ osmolality: There are several mechanisms by which sodium reabsorption or can be affected. The most important are: → detected by osmoreceptors of the hypothalamus → ↓ ADH secretion 1. The renin–angiotensin–aldosterone system The response to hypokalaemia in the collecting duct is to stimulate 2. Atrial natriuretic peptide the uptake of potassium from the filtrate by activating the potassium One of the end points of the activation of the renin-angiotensin ion-hydrogen ion exchange pump. This secretes hydrogen ions into system is the release of aldosterone. Aldosterone increases sodium the collecting duct in exchange for reabsorbing potassium ions. This reabsorption by increasing the number of sodium channels and the is why hypokalaemic patients are often alkalotic. This pump is also sodium pumps which drive the reabsorption of sodium in the DCT stimulated by acidosis and is one of the reasons why acidotic patients and the collecting duct. are often hyperkalaemic. The kidney can maintain normal serum potassium concentration Atrial natriuretic peptide is released in response to atrial stretch, a down to low GFRs. When the kidneys potassium handling ability sign of salt and water overload. This increases the sodium excretion finally fails the patient becomes hyperkalaemic due to the low by inhibiting the renin-angiotensin system (see above) and by direct quantities of blood being filtered and the inability of the kidney to inhibition of the reabsorption of sodium in the collecting duct. respond by secreting increased levels of potassium. Faecal excretion of potassium is up-regulated to help maintain serum potassium as POTASSIUM BALANCE the kidney fails. Potassium is freely filtered by the glomerulus. Almost all of it is then reabsorbed by the PCT. The mechanism at this point is not regulated TOXIN REMOVAL and does not respond to differing plasma potassium concentrations. Toxins are removed by two mechanisms: The DCT and collecting ducts are responsible for regulating 1. Filtration potassium balance by increasing secretion or reabsorption. 2. Secretion There are two clinically important mechanisms for potassium exchange. Aldosterone stimulates potassium secretion by increasing Most water soluble toxins such as creatinine are freely filtered and sodium reabsorption. Sodium is reabsorbed in exchange for potassium not reabsorbed. Therefore the levels should remain constant and at by an active transporter. Thus drugs such as spironolactone which non-toxic levels in the blood unless ingestion, production or GFR antagonise aldosterone can cause hyperkalaemia. changes.

Update in Anaesthesia | www.worldanaesthesia.org page 64 Some toxins are removed from the blood by active secretion in the reverse - combines with water to form bicarbonate, PCT. Drugs such as diuretics and trimethoprim are removed in this which is reabsorbed into the blood stream, and a hydrogen ion, way. which is recycled to be used to reabsorb another bicarbonate ion. The mechanism of bicarbonate reabsorption does not cause a net loss CALCIUM AND PHOSPHATE HOMEOSTASIS of hydrogen ions and does not excrete any of the acid produced by The kidney plays a major role in calcium homeostasis, along with the the body. skeleton and intestine. The intestine allows calcium and phosphate to be absorbed from the diet. The skeleton is the store of calcium. The distal nephron then reclaims any of the bicarbonate that remains The kidney has two roles: in the filtrate after passing through the PCT.

1. The activation of (via addition of a second hydroxyl Although when the filtrate reaches the collecting duct it is acidic, group) which then facilitates calcium absorption from the this is because of the reabsorption of bicarbonate not the excretion digestive tract. of acid. As stated previously there is an excess of acid generated by metabolism that the body needs to excrete. Although the vast majority 2. The tubular reabsorption and excretion of calcium and phosphate is achieved by carbon dioxide excretion by the lungs, an important respectively under the influence of . fraction (particularly phosphate and sulphate ions) is excreted by the Vitamin D stimulates the absorption of both calcium and phosphate collecting duct. Hydrogen ions are actively secreted by the hydrogen from the intestine and is part of the feedback mechanism which ion-potassium ion antiporter (see above). This would result in a sharp controls plasma levels of these ions. increase in the acidity of the urine if the hydrogen ions were not buffered. As all the bicarbonate has been reabsorbed, the hydrogen ACID BASE BALANCE ions are buffered primarily by ammonia, created from in Maintenance of a constant pH is very important for the body as the renal tubular cells and filtered phosphate ions. many of our enzyme systems are very pH sensitive. Both acids and alkalis are generated from the diet either by direct ingestion or by generating an acid or an alkali after metabolism. There is usually a net acid production. Bicarbonate is the main buffer in the human body. As almost 100% of bicarbonate is filtered by the kidney, to help maintain the pH in the body the bicarbonate must be reabsorbed. This is mainly done by the PCT which acidifies the urine. The pH falls from 7.3 to 6.7 along the length of the PCT.

The PCT reabsorbs bicarbonate by secreting hydrogen ions into the lumen of the tubule. The enzyme catalyses the conversion of the hydrogen ion and the bicarbonate ion into water and carbon dioxide with in the tubule. The carbon dioxide then diffuses back into the where carbonic anhydrase catalyses the Figure 6. Regulation of erythropoiesis by erythropietin ERYTHROPOIESIS The kidney responds to and decreased red blood cell mass (decreased oxygen carrying capacity) by releasing which stimulates the to produce more red blood cells (Figure 6).

CONCLUSION This article provides an overview of the major functions ofthe kidney. A clear understanding of these concepts is essential for safe administration of drugs during anaesthesia, particularly in those with impaired renal function. A logical knowledge of the physiology of the renal system allows recognition and appropriate management of patients with renal failure, particularly in patients with critical Figure 5. Bicarbonate reabsorption in the PCT illness.

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